CN101198672A - Photoluminescent silica-based sensors and methods of use - Google Patents

Photoluminescent silica-based sensors and methods of use Download PDF

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CN101198672A
CN101198672A CN 200680021750 CN200680021750A CN101198672A CN 101198672 A CN101198672 A CN 101198672A CN 200680021750 CN200680021750 CN 200680021750 CN 200680021750 A CN200680021750 A CN 200680021750A CN 101198672 A CN101198672 A CN 101198672A
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photoluminescent
silica
based
sensors
methods
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CN 200680021750
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Chinese (zh)
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CN101198672B (en )
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乌尔里希·魏斯纳
埃里克·赫茨
塔拉·C·泽戴科
安德鲁·A·伯恩斯
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科内尔研究基金会
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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/62Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64Fluorescence; Phosphorescence
    • G01N21/6428Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/62Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64Fluorescence; Phosphorescence
    • G01N21/6428Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6439Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks
    • G01N2021/6441Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks with two or more labels

Abstract

本发明涉及包含氧化硅基的核及至少一种光致发光染料的感应颗粒。 The present invention relates to an induction core and containing silica-based particles of at least one photoluminescent dye. 该氧化硅基的核可包含多个孔,而该至少一种光致发光染料可包括对其环境和分析物不敏感的参比染料以及对所述环境或分析物敏感的感应染料。 Endorse the silicon oxide comprises a plurality of holes, and the at least one photoluminescent dye and their environment can comprise analyte insensitive reference dye and the environment or the induction analyte sensitive dye. 该感应颗粒可用来在体内或体外感测生物或非生物系统中未知环境状态或分析物。 The sensor particles can be used in vivo or in vitro biological or non-biological system sensing unknown environmental conditions or analytes.

Description

氧化硅基光致发光感应物及^f吏用方法 Photoluminescence sensing the silicon oxide thereof and a method officials ^ f

技术领域 FIELD

本发明涉及氧化^圭基颗粒,并且更具体地涉及含有适于用作感 The present invention relates to oxide-based particles ^ Kyu, and more particularly relates to a sense suitable for use as

测剂(sensing agent)的光致发光物质的氧化石圭基颗粒。 Test agent (sensing agent) oxide based particles kyu stone photoluminescent material. 背景技术 Background technique

近年来,基于光致发光成像的纟支术基本朝向高分辨率、实时、 分子水平分析的方向发展,以直观化并获知生命及其过程。 In recent years, photoluminescence imaging technique Si branched substantially toward a high resolution, real time, analysis of the molecular level of development, and is known to visualize their life processes. 基于光致发光的分析的魅力源于其优异的对比度、高特异性以及快的响应时间。 Based on the analysis of the photoluminescence attractive due to its excellent contrast, high specificity, and fast response times.

尽管大多数光致发光染料被设计成对其环境不敏感,但各种具有特异亲和性并响应于化学分析物或环境刺激物的染料已经被合成出来。 Although most photoluminescent dyes are designed to be insensitive to the environment, but having a specific affinity of various chemical analytes in response to environmental irritants or dyes has been synthesized. 例如,已经将某些类型的光致发光染料游离地用于溶液中作为响应化学分冲斤物或环境刺激物的感应物。 For example, it has been certain types of photoluminescent dyes used in solution as the free response to a chemical induction was pounds red points or environmental stimuli.

虽然每文感和不每文感的光致发光化合物通常都是游离地用于溶液中,但是在一些情况下,这些染料已被结合到感应平台(platform) 如光学纤维、薄膜及膜上。 Although each sense of each text and non-text flu photoluminescent compound is usually used in free solution, but in some cases, these dyes have been incorporated into the sensor platform (Platform) optical fibers, films and membranes. 感应平台的组分以及光致发光染料的特性,除了确定观察其感应能力的未知状态的类型外,还会影响染料的性能。 Component and a characteristic photoluminescent dyes sensing platform, in addition to determining the unknown state to observe its ability to types of induction, but also affect the performance of the dye.

需要一种环境或分碎斤物的感应物,其可以最优^f匕光致发光染^j" 的可变的性能并且在多种环境中感应未知状态。 发明内容 A need for a sub-environment or induction thereof was broken pounds, which may be the optimal performance of the variable f ^ dagger photoluminescent dye ^ j "unknown state and sensing in a variety of environments. SUMMARY OF THE INVENTION

本发明涉及用于检测各种环境状况和分析物的改进的感应颗 The present invention relates to a particle sensor for detecting environmental conditions and improve various analytes

法。 law. 、 、' I ; ' 、 I ,, 'I;', I

简要的i兌,本发明的感应颗粒包4舌核和至少一种光致发光染料。 I against brief, the present invention is responsive particles packet core 4 and at least one tongue photoluminescent dye.

在一些具体实施方式中,核是氧^:石圭基纳米颗米i,而至少一种光致发光染料包括参比染料和感应染料,其中至少之一可以与核共价连接。 In some embodiments, the core is oxygen ^: stone particles Nano Gui m i, and the at least one photoluminescent dyes include dyes sensing and reference dye, which may be connected with at least one nuclear covalently. 参比染料可以位于核内而感应染料可位于核的至少一部分表面上。 Reference dye may be located in the nucleus is induced on the surface of the dye may be located at least part of the core. 可替换地,参比染料和感应染料可位于核表面或在核的外围。 Alternatively, the reference dye and the sensor dye may be positioned on the peripheral surface of the core or nucleus. 而且,氧化硅基颗粒可包括围绕核的氧化硅基的壳,其中参比染料位于核内并且氧化硅基的壳介于参比染料和感应染料之间。 Further, the silicon oxide particles may include silica-based shell surrounding the core, wherein the core and the reference silica-based shell is interposed between the reference dye and the sensor dye dye is located. 在其它具体实施方式中,参比染冲牛和感应染一+之一的每个感应颗粒包 In other embodiments, the reference packet responsive particles each transfection and induction bovine red dye of one of a +

括在约1.0至1000.0个之间的染料分子,并且参比染料和感应染料 Including between about 1.0 to 1000.0 dye molecules, and the reference dye and the sensor dye

响应于单波长或多波长激发源而发射光子。 Response to a single or multi-wavelength excitation source and emission of a photon. 参比染料和感应染料响应适当激发的峰值发射波长通常被足够的间隙所分开,从而逐个地辨别它们的发射峰。 Appropriate reference dye excitation and response induced dye normally peak emission wavelength are separated by a sufficient gap to individually discern their emission peaks.

在其它具体实施方式中,核包括多个孔,其中至少一个孔具有 In other embodiments, the core comprises a plurality of apertures, wherein the at least one aperture having

在约0.1 nm至约100.0 nm之间的直径,并且更具体i也在约2.0 nm 至约50.0 nm之间。 A diameter between from about 100.0 nm to about 0.1 nm, and more particularly between about i are about 2.0 nm to 50.0 nm. 氧化硅基颗粒的直径可在约1.0 nm至约250.0 Diameter silica-based particles can be from about 1.0 nm to about 250.0

腿之间。 Between the legs.

本发明的方法包才舌4吏用感应颗并立来感应未知的环i竟状况或分析物。 The method of the present invention only packet 4 officials tongue pieces side by side to sense an induction loop i actually unknown conditions or analytes.

在一种具体实施方式中,该方法包4舌以下步艰《:才是供至少一种含有两种或多种光致发光染4+的氧化硅基颗粒,将该至少一种氧化硅基颗粒f I入到包括未知状态或分析物的环境中,将该至少一种氧化硅基颗粒暴露于激发光子,以使该两种或多种光致发光染料中的每一个发射光子,记录由该两种或多种光致发光染料发射的光子, 以及从这些数据来确定未知的环境状态或分析物。 In a specific embodiment, the method the following steps difficult tongue 4 ": is for at least one silicon-containing oxide particles of two or more photoluminescent dye 4+, the at least one silicon-oxide f I comprising particles into an unknown state, or environmental analytes, at least one of the silicon oxide particles are exposed to excitation photons, such that each of the two or more luminescent dyes emit photons in the photo, the recording the two or more photons emitted photoluminescent dye, and from these data to determine the unknown environmental conditions or analytes. 该方法可以进一步包括在存在已知的环境状态或分析物的情况下用光子激发该两种或多种光致发光染料,并比4交在已知的环境状态或分析物的存在下得到的该两种或多种光致发光染料的发射波。 The method may further comprise the excitation of the two or more photoluminescent dyes with photons in the presence of a known environmental condition or analyte, and with the presence of more than 4 in a cross-known environmental condition or analyte the two or more waves emitted photoluminescent dye. 在这些情况下,在已知的环境状态或分析物存在下得到的发射可用来产生对照tt据, 其与已知的状态或分析物是相关的。 In these cases, resulting in a known environmental condition or analyte used to generate the control tt transmit data, or a state which is known analyte is relevant. 因此,测定步-骤可包括使用这些对照教:据来确定未知状态或分析物。 Therefore, the determination step - step may include the use of these controls teachings: According to determine the unknown condition or analyte. 确定步骤还可以包括同时探寻(interrogation)其(即,多种感应染料)发射峰可去巻积(deconvolve )、以获得多个未知状态或分析物的状况的多种感应染料。 Determining may further include the step of simultaneously exploring (interrogation of) thereof (i.e., more dye inductive) convolving go emission peak (Deconvolve), to get the status of multiple unknown states or multiple analyte sensing dyes.

在另一个具体实施方式中, 一种测定生物体中未知状态的方法包括以下步骤:提供含有能发射光子的感应染料的氧化硅基纳米颗粒,将该氧化硅基纳米颗粒插入到生物体中,用光子激发该感应染料,测定感应染料的光致发光发射,以及测定生物体的未知状态。 In another embodiment, an assay organism unknown state comprising the steps of: providing a silicon-containing oxide-based nanoparticles capable of emitting photons induced dye, the silica-based nanoparticles inserted into the organism, the dye photon excitation sensing, measuring photoluminescence emission unknown state, and the measurement of the living body sensing dye. 感应染纟十可在红外或近红外波长处发射光子。 Si ten induction dye can emit photons in the infrared or near-infrared at wavelengths. 氧化硅基纳米颗粒可;故置在生物体的细胞、组织、血液或其它体液中。 Silica-based nanoparticles can; it is set in a cell, tissue, blood or other body fluids of an organism.

附图说明 BRIEF DESCRIPTION

通过附图来描述要求保护的本发明的一些具体实施方式。 Some embodiments of the present invention will be described by reference claimed. 应该理解,没有必要绘制的图形及对理解本发明没有必要的细节或其他难以理解的细节都被忽略了。 It should be understood, and there is no need graphic details of the present invention is not necessary to understand the details of drawing or other difficult to understand are ignored. 当然,应该理解,本发明不必限制于这里所描述的特定具体实施方式。 Of course, it should be understood that the present invention is not necessarily limited to the particular embodiment described herein. 图1A是本发明氧化石圭基颗粒的一个具体实施方式的局部剖面透视图; 1A is a partially cutaway perspective view of a specific embodiment of the present invention, oxide-based particles Kyu stone;

图IB是本发明氧化硅基颗粒的另一个具体实施方式的局部剖开的透一见图; FIG IB is a partial another specific embodiment of the present invention, the silicon oxide particles is taken through a Figure;

图1C是本发明氧化石圭基颗粒的又一个具体实施方式的局部剖开的透^见图; FIG 1C is a partial yet another particular embodiment of the present invention, oxide-based particles Kyu stone taken through Figure ^;

图ID是本发明氧化硅基颗粒的又一个具体实施方式的局部剖开的透一见图。 Fig ID is a further particular embodiment of the silicon oxide particles of the present invention, partially broken away of the embodiment of a see through.

图2A是图1A的氧化硅基颗粒的扫描电镜图像; FIG 2A is a SEM image of the silicon oxide particles. 1A;

图2B是图1B的氧化硅基颗粒的扫描电镜图像; FIG 2B is a SEM image of the silicon oxide particles. 1B;

图2C是图1C的氧化硅基颗粒的扫描电镜图像; FIG 2C is a scanning electron micrograph of FIG. 1C is a silicon oxide particles;

图3是在已知的pH下使用本发明的氧化硅基颗粒的光致发光强度对峰值波长的曲线图,以及 FIG 3 is a graph of the peak wavelength of photoluminescence intensity using a silicon oxide particles of the present invention at a known pH, and

图4是校准曲线,其基于在图3中收集的数据,绘出了参比和感应染料与pH相关的峰值波长发射的比率。 FIG 4 is a calibration curve based on the data collected in Figure 3, it depicts the ratio of the reference and sensor dyes associated with the peak wavelength emitted pH.

具体实施方式 detailed description

本发明的氧化硅基颗粒通常是纳米颗粒并包含氧化硅基的核以及两种或多种光致发光染料。 Silica-based particles of the present invention generally comprise nanoparticles and silica-based core and two or more photoluminescent dyes. 如这里Y吏用的,术语核是指中心或基本部分。 The Y officials herein, the term refers to the center or core portion substantially. 用于形成氧化硅基基体(matrix)的氧化硅可具有通式R4—nSiXn,其中X可以是可水解基团,如乙氧基、曱氧基或2-曱氧基-乙氧基,R可以是有机基团(例如甲基或乙基)并且n是1至4 Silicon oxide for forming a silicon oxide-based matrix (Matrix) may have the general formula R4-nSiXn, wherein X may be a hydrolyzable group such as ethoxy, or 2- Yue Yue group - ethoxy, R may be an organic group (e.g. methyl or ethyl) and n is 1 to 4

的整数。 Integer. 两种或多种光致发光染料包括参比染料和感应染料。 Two or more photoluminescent dyes comprise a reference dye and a sensor dye. 如这里使用的,术语参比染料是指这样的染料,其对环境和/或任何存在于其中的分析物基本不敏感或当在不同环境下暴露于激发光子时呈现出相同或基本相同光子发射。 As used herein, the term reference dye refers to a dye which substantially insensitive to the environment and / or any analyte present therein or when different environmental exposure to excitation photons exhibit the same or substantially the same photon emission . 术语感应染料是指任何对其环境和/或分4斤物壽文感的或有响应的,或在不同环境或分析物下暴露于光子时呈现出不同的光子发射的染料。 The term refers to any dye-dye induction different photon emission exhibit their environment and / or sub-TING was 4 pounds sense or responsive to, or in different environments or analytes exposed to photons. 在一些具体实施方式中,参比染料和感应染料可以与氧化石圭基基质共价连接。 In some embodiments, the reference may be connected to the stone Kyu oxide based matrix and induction of covalent dye dyes. 在其它具体实施方式中,染料可以在无共价键的情况下通过物理捕获而限制在氧化硅基基体中或被吸附在基质的表面上。 In other embodiments, the dye may be restricted to the silicon oxide-based matrix or adsorbed on the surface of the substrate by physical entrapment without covalently case.

在一种具体实施方式中,将参比和感应染料与氧化硅基基体结 In a specific embodiment, the reference and sensing dye junction silicon oxide-based matrix

合在一起可增强染料的亮度并阻止光致褪色(即,染料保持明亮的时间延长)。 Together can enhance the brightness and to prevent the dye photobleaching (i.e., dye retention bright prolonged). 在这些具体实施方式中,本发明的氧化硅基颗粒与溶液中的游离染料相比表现出增强的亮度水平,例如通过光致发光相 In these embodiments, the silicon oxide particles to the free dye in solution compared to the present invention exhibit enhanced brightness level, for example by phase photoluminescence

关光:i普测量的。 Light off: i P measured.

在另一个具体实施方式中,氧化硅基基体包括孔或缝隙,使得液体或分析物可以渗入到氧化石圭基基体中,并且直冲妄与位于其中的感应染4+相互作用。 In another specific embodiment, the silicon oxide-based matrix comprises a hole or a slit, such that the liquid can penetrate to the analyte or stone kyu oxide based matrix, and wherein the straight jump located 4+ staining induced interactions. 以这种方式,感应能力可以增强。 In this way, the sensing capability can be enhanced. 3L通常包括「 在约O.lnm至约100.0nm之间的直径。孔大小可表现出不同的分布, 大小范围在2.0nm至约50nm及以上。 3L typically include "O.lnm diameter between about 100.0nm to about the aperture size may exhibit different distributions, in the size range from about 2.0nm to 50nm or more.

在另一个具体实施方式中,氧化硅基基体的使用可以用单激发波长激发两种或多种染料。 In another specific embodiment, the silicon oxide-based matrix of two or more dyes may be excited with a single excitation wavelength. 对于具有可区分开的发射峰的参比和感应染料,改变每一颗粒中每种染料的分子数量可使通常需要多个激发波长的染料结合物响应于单激发波长。 For a peak emission region may separate reference and sensor dyes, to change the number of molecules of each dye in each particle can generally require multiple excitation wavelengths dye conjugate in response to a single excitation wavelength. 例如,如果参比染料为了发射比感应染料需要更长的激发波长,那么附加的参比染料分子可与氧化硅基基体结合来增强其相对吸收,使得这两种染料可测量地响应于相同的激发波长。 For example, if the reference dye to the dye than the induced emission takes longer excitation wavelengths, additional reference dye molecules can be bonded to a silicon oxide-based matrix to increase its relative absorption, so that these two dyes measurably in response to the same excitation wavelength. 氧化硅基基体每个颗粒可以结合约1.0个至约1000.0个染泮牛分子,通常在2.0个至100.0个染谇牛分子。 A silicon oxide based matrix may be incorporated per particle from about 1.0 to about 1000.0 dye molecules Pan cattle, usually 2.0 to 100.0 dye molecules bovine insult.

在又一个具体实施方式中,氧化石圭基基体可包括多于一种的感应染料用于感应多于一种的环境状态或分析物。 In yet another embodiment, the oxide based matrix may include stone Kyu more than one sensor for sensing more than one dye environmental conditions or analytes. 假定被引入的染料的发射波长是足够分开的从而可分辨不同的发射峰,约一种至约七 Assumed that the dye is introduced into the emission wavelengths are sufficiently separated so that different emission peaks can be distinguished, from about seven to about one kind of

结合用于不同的感应应用。 In combination with different sensing applications.

本发明的氧化硅基颗粒也可引入添加物。 Silica-based particles of the invention may be incorporated additive. 可以出于各种目的在颗粒表面设置超顺》兹性材料的核,如纳米尺寸的氧化铁或其它》兹性合金或氧化物和/或一种或多种大量的官能团。 Can be provided for various purposes superparamagnetic particle surface "hereby nuclear materials, such as nano-sized iron oxide or other" hereby alloy or oxides and / or one or more of a large number of functional groups. 例如,颗粒可与抗体或治疗剂结合以用于确定和治疗疾病的爿大态或症一犬。 For example, the particles may be combined for use in determining and treating a disease state or disorder valves a large dog with an antibody or therapeutic agent. 治疗剂可以—皮吸收到氧化石圭基基体的孔中或涂在颗粒的表面上。 The therapeutic agent may - percutaneous absorption into the pores of the stone Kyu oxide based matrix or coated on the surface of the particles.

最终氧化硅基颗粒的表面可以用各种表面修饰剂,包括胺、抗体、樣丈生物、病毒、酶、受体、半抗原、激素、或其组合加以功能化。 Final oxidation of the silicon surface of the particles may be a variety of surface modifying agents include an amine, an antibody, a biological sample Zhang, viruses, enzymes, receptors, haptens, hormones, or combinations thereof to be functionalized. 氨基的使用,如氨丙基和曱基氨丙基基团,产生可吸引细胞表面负电荷的正表面电荷。 An amino group using, such as aminopropyl group and Yue aminopropyl groups to produce a positive surface charge may be attracted to the negatively charged cell surface. 烷基的使用,如曱基或十二烷基链,产生无电荷表面,使颗粒可存在于疏水环境中-如在细胞膜里。 An alkyl such as an alkyl chain or dodecyl group Yue, produce no surface charge, the particles may be present in a hydrophobic environment - such as in cell membranes. 而且, 可以用功能性的连接于氧化硅的基团与多种物质反应,包括聚合物 Moreover, with a functional group connected to a plurality of reacting with silicon oxide, a polymer comprising

例如:聚乙二醇(PEG)、交联剂以及其它表面修饰剂如羧酸、酉旨类或生物素,其可用于将其它部分(基团)连接到颗粒表面,包括肽、 DNA、抗体以及抗生物素蛋白/链霉亲和素。 For example: polyethylene glycol (PEG), a crosslinking agent and other surface modifying agents such as carboxylic acids, biotin or unitary purpose type, which can be used in other portions (group) is connected to the particle surface, including peptides, DNA, antibodies and avidin / biotin streptavidin. 表面》爹饰剂可包括围绕颗粒的层,其对某些分析物是选择性可渗透的。 Surface "Dad agent decorative layer surrounding the particles may comprise, for certain analytes which are selectively permeable. 该层介于感应染料与环境之间。 The dye layer is interposed between the sensor and the environment.

用合适的表面改性剂功能化颗粒的表面使得颗粒可在多目标环境中使用。 Suitable surface with a surface modifier functionalized particles so that the particles can be used in a multi-target environment. 例如,疏水涂料的加入使颗粒可分散在疏水的环境里。 For example, addition of a hydrophobic coating material particles can be dispersed in a hydrophobic environment.

用,定义为特别需要的相互作用的可能性相对增大。 Used, defined as the probability of an interaction with special needs relatively increased. 实例包括使用至少一种对细胞表面抗原具有亲和性的抗体使颗粒表面功能化,和 Examples include using at least one antibody having an affinity for cell surface antigen particles surface functionalized, and

/或^f吏用含有生物素和抗生物素蛋白A连霉亲和素的涂料,其优选在目标环境中与生物素相互作用。 / ^ F officials or with protein containing biotin and avidin attached A streptavidin coating, which preferably interact with biotin in the target environment.

如上所述,该两种或多种光致发光染^牛可包4舌参比染料和感应染料。 As described above, the two or more photoluminescent dye ^ bovine tongue 4 may be coated dye and the reference dye induction. 参比染料和感应染料的发射峰值波长通常被足够的波长间隙分开从而在同一波长下激发时能单独地分辨它们的峰。 Reference induced emission peak wavelength dye and the dye is typically separated a sufficient clearance so that the wavelength at the same wavelength of excitation can be individually resolved peaks thereof.

参比染泮+通常一皮螯合(sequester)在氧化义圭基颗粒内部, 一般在其核中。 Reference is usually a leather dyed Pan + chelate (Sequester) oxide particles inside the sense Kyu group, generally in its nucleus. 尽管参比染冲牛对其环境和分析物是基本不敏感的,但是将参比染冲+螯合在颗粒内部可作为预防4普施来阻止在确实存在翁: 感性时与目标环境或分析物的相互作用。 Despite their environment and bovine red dye analyte is substantially insensitive to the reference, but the reference impulse + chelating dye inside the particles can be administered as a prophylactic to prevent 4 P does exist Weng: target environment or inductive and Analysis interactors. 合适的参比染料包括,但不限制于,如下: Suitable reference dyes include, but are not limited to, the following:

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所谓的Megastokes™染并牛在这里定义为其激发和发射波长之间表现出的差值在约30.0 nm到约200.0 nm之间的染料。 Megastokes ™ dye and a so-called cow here defined as the excitation and emission wavelengths exhibits a difference between the dye between about 30.0 nm to about 200.0 nm.

感应染料一般放置在氧化硅基颗粒的表面上或附近,用来增强其与环境和/或<壬4可分冲斤物的相互作用。 Induction dyes are generally placed on the surface of the silicon oxide particles, or near, to enhance its environment and / or interaction <azelaic 4 pounds was divided into red. 在这种结构中,感应染冲+更易于与需要研究的环境状态或分析物直接接触。 In this configuration, the sensing dyed red + easier to be studied and the environmental conditions or direct contact with the analyte. 感应染料的发射经受环境或分析物刺激。 Induced emission dye or analyte subjected to environmental stimuli. 例如,依赖于环境的pH, pH感应染料基于感应染料电子状态的变化,通过光子的增加或减少,表现出变化的发射光i普。 For example, depending on the pH of the environment, sensing pH sensing dye-based dye electron state change, by increasing or reducing the photons, emitted light exhibits a change P i. 金属离子的存在通过淬灭(quenching)该感应染冲+而引起发射的减少。 Presence of metal ions by quenching (quenching) dye red + the induced emission caused reduced.

下表是许多适合的多种感应染冲牛以及其对环境或分析物壽丈感性的非详尽列表。 The following table is a lot of sense for a variety of dyed red cow as well as its non-exhaustive list of environmental or analyte husband emotional life.

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所谓被笼住的染冲牛(caged dye)可作为感应染冲牛。 The so-called muzzle bovine red dye (caged dye) can be used as an induction bovine red dye. 一皮笼住的染料是其光致发光状态被它们的环境活化的一类光致发光染料中。 A muzzle leather dyes are photoluminescence activated state for a class of their environment photoluminescent dye. 换句话说,束绰染料以非-光致发光状态进入其工作环境并被改变其染料化学结构的外部事件"打开"。 In other words, the beam Chuo dye non - photoluminescent state into its working environment and changes its chemical structure external event dye "open." 被笼住的染料典型通常包括将特定基团共价连^妾至主要的共轭环状结构。 Typically the muzzle dyes generally comprise a particular group is covalently attached to the primary concubine ^ conjugated cyclic structure. 当共价连4妾由于环境刺激物而断裂时活4匕就会发生。 When covalently Greenwood 4 due to environmental irritants dagger broken concubine 4 occurs. 例如,试卣灵(7-羟基-phnoxazin-3-酮) 是利用可断裂的醚连接的被笼住的染料家族的母体染料(parent dye )。 For example, the test wine container spirit (7-hydroxy--phnoxazin-3- one) using ether breakable connection being muzzle dye family dye precursor (parent dye).

染料可以以多种设置引入到氧化硅基基体中。 Dyes may be introduced to the silicon oxide-based matrix to various settings. 参照图1A、图1B、图1C和图ID,示出了本发明的氧化硅基颗粒的不同结构。 Referring to FIGS. 1A, 1B, 1C and ID, shows the different configurations of the silicon oxide particles of the present invention. 如图1A所示,氧化硅基颗粒包括具有氧化硅基基体及参比染料的内 1A, the silicon oxide particles include silicon oxide-based matrix and the reference dye

核10、中间氧化石圭基的壳12,以及含有感应染冲牛的外壳14。 Core 10, the intermediate oxide group Kyu stone shell 12, and a housing 14 containing a sensing dyed red cattle. 在该具体实施方式中,中间氧化石圭基的壳介于参比染坤牛与感应染冲牛之间。 In this particular embodiment, the intermediate oxide groups Kyu stone shell interposed between the reference dye than red dye induction Kun bovine cattle. 中间氧化石圭基的壳可独自包括氧化石圭基材料而没有光致发光染料的存在,或存在最小量的光致发光染料(如按重量计少于5% )。 Intermediate oxidation stone Kyu groups shell may comprise oxide alone kyu stone based material without the presence of photo-luminescent dye, or the presence of a minimum amount of dye photoluminescence (e.g., less than 5% by weight). 如图1B所示,氧化石圭基颗粒包括含有氧化石圭基基体及参比染坤+的内核IO、和含有感应染泮+的外部壳14。 1B, the oxide-based particles comprising stone Kyu Kyu stone containing oxide based matrix and the reference dye Kun core + IO, and an outer housing 14 containing a sensing dye Pan +. 如图1C所示,氧化石圭基颗粒包括含有氧化石圭基基体的内核10、含有参比染并+的第一壳16、 包围第一壳并含有感应染料的第二壳14。 1C, stone oxide particles comprising a core containing groups Kyu stone Kyu oxide-based matrix 10, the first shell contains a reference dye and + 16 surrounding the first shell and a second shell comprising 14 sensing dye. 如图1D所示,氧化硅基颗粒包括具有氧化石圭基基体的内核10、含有参比染才牛的第一壳16、 包围第一壳并具有另一个氧化硅基基体的中间壳12,以及包围该中间壳并含有感应染料的外壳14。 1D, the silicon oxide particles having a core comprising a stone Kyu oxide based matrix 10, containing only reference transfected cattle first shell 16, surrounding the first shell and intermediate shell further having a silica-based substrate 12, and surrounds the intermediate shell and the housing containing the sensor 14 dye. 在这些具体实施方式中,核的直径可在约2.0nm至几十孩史米之间,并且通常在约25.0nm至200.Onm 之间。 In these embodiments, the core diameter may be between about 2.0nm to several tens of meters child history, and typically between about 25.0nm to 200.Onm. 第一壳和随后的壳的厚度可在约1 .Onm至约400.0nm之间, 并且通常在约10.0nm至约50.0nm之间。 The first and subsequent shell thickness of the shell may be between about 1 .Onm to about 400.0nm, and typically about between about 10.0nm to 50.0nm. 第一壳和随后的壳可以覆盖颗4立约10.0%至约100.0%的表面积。 The first and subsequent shells may cover shell particles 4 stand about 10.0% to about 100.0% of the surface area. 因此,颗4立的大小可在约10.0 nm至几十孩么米之间,并且更具体;也在约10.0 nm至约1.0微米之间。 Thus, the size of the particles stand 4 may be between about 10.0 nm to several tens of meters what child, and more specifically; also between about 10.0 nm to about 1.0 microns.

存在许多用来合成本发明的氧化硅基颗粒的方法。 Many methods for the synthesis of silicon oxide particles of the present invention. 例如,可使用溶胶-凝胶法来产生颗粒。 To produce gel particles - e.g., a sol may be used. 溶胶-凝胶化学使得氧化硅基颗粒的合成可在温和的条件下进行,如室温和不使用有害化学物质。 Sol - gel chemistry such that the silicon oxide particles can be synthesized under mild conditions, such as room temperature without the use of harmful chemicals. 可替换地,反胶束可用作反应器用于颗粒的合成。 Alternatively, reverse micelles used as a reactor for the synthesis of particles. 反胶束是由两亲的表面活性分子介导的,极性水相在疏水溶剂中的稳定混悬液。 Reverse micelles of surfactant molecules is mediated by the amphipathic polar aqueous phase in a hydrophobic solvent in a stable suspension.

St6ber溶胶-凝胶法一般可获得含有共价连接参比和感应染料的氧化硅基颗粒。 St6ber sol - gel method comprising covalently linked commonly available reference and sensing dye silicon oxide particles. 通常,本发明的氧化硅基颗粒可使用SU3ber溶胶 Typically, the silicon oxide particles of the present invention can be used SU3ber sol

物混合来形成活性光致发光有枳^圭烷化合物,其可以,皮共缩合而形 Orange photoluminescence activity have Kyu ^ alkyl compounds which can be co-condensation of skin-shaped product formed by mixing

硅烷混合而将感应染料结合到核上。 Mixing the silane binding dye is induced to the core.

然而,溶"交-凝力交法可才艮据颗粒所需的结构而改变。如上所述, 本发明的氧化硅基颗粒可表现出各种构造,包括具有氧化硅基基体 However, soluble "cross - coagulation force method can deposit only the desired particle structure according Gen changed as described above, the silicon oxide particles of the present invention may exhibit various configurations, including a silicon oxide-based matrix.

有氧化硅基基体的内核、含有参比染料的第一壳及包围第一壳并含 Silicon oxide-based matrix core comprising a first shell and reference shell surrounding the first dye and containing

有感应染^h的外壳(1C和图1D)。 ^ H induction dye housing (1C and FIG. 1D).

图1A中的氧化^圭基颗粒的制备包括核的合成、随后的氧化;圭中间壳的生长以及富含感应染料的氧化硅壳的形成。 Preparation of ^ Kyu oxide based particles in Fig. 1A comprises a synthetic core, subsequent oxidation; Kyu formed intermediate shell growth and induction of the dye-rich silicon oxide shell. 核的合成一般是三个步骤。 Synthesis of the core is generally three steps. 首先,在惰性气氛下,使硅烷化合物与参比染料以硅烷:参比染料为约50:1的摩尔比在脱气乙醇中结合,以形成光致发光硅烷化合物。 First, under an inert atmosphere, and a silane compound to the silane reference dye: reference dye is from about 50: Binding in degassed ethanol 1 molar ratio, to form a silane compound photoluminescence. 然后,将该产物(参比染料结合物)在环境条件下加入到氨和水的无水乙醇溶液中,同时用力"t觉4半。4妄着,迅速地力口入氧化硅前体,如四乙氧基硅烷,从而产生最终的反应溶液,其中参比染料结合物、氧化硅前体、氨及水的浓度是1.7 x 10 —5M、 0.05 M、 0.2M及0.855 M。 4吏该反应进4亍12-18小时,^寻到富含染^F的石圭酸盐核,直径为约5.0nm。在该溶液中,l菱'("曼地加入另外的氧化硅前体来生长氧化硅壳,所加量为约5.55 x 10 —6\1/分钟,达到参比染泮+结合物、氧化石圭前体、氨水及水分别为1.7 x 10 —5M、 1.055 M、 0.5 M及0.855 M的最终反应条件。 Then, the product (reference dye conjugate) was added to a solution of ammonia in absolute ethanol and water under ambient conditions, with vigorous "t sleep 4 .4 half the jump, fast mouth fertility silicon oxide precursor, such as tetraethoxysilane, thereby producing a final reaction solution, wherein the concentration of the reference dye conjugate, silica precursor, ammonia and water is 1.7 x 10 -5M, 0.05 M, 0.2M and the reaction was 0.855 M. 4 official 4 into the right foot for 12-18 hours, transfected ^ F ^ find a rich stone Kyu acid nucleus, a diameter of about 5.0nm. in this solution, l Link '( "Man adding additional silicon oxide precursor to grow silica shell, added in an amount of from about 5.55 x 10 -6 \ 1 / min, to reach the reference dye conjugate Pan +, stone Kyu oxide precursor, ammonia and water were 1.7 x 10 -5M, 1.055 M, 0.5 M 0.855 M and the final reaction conditions.

为了制备核/壳颗粒用于与感应染料结合,将颗粒对乙醇进4亍一次约24小时的渗析。 To prepare the core / shell particles used in combination with sensing dye, the particles of the primary alcohol into the right foot 4 to about 24 hours of dialysis. 然后稀释渗析溶液以避免颗粒在感应染料偶联反应过程中的团聚。 Dialyzed solution was then diluted to avoid particle agglomeration in the induction of a dye during the coupling reaction. 使用以上用于参比染料的相同方法将感应染料与硅烷结合来形成感应染料结合物,但在这种情况中摩尔比低得多(即,硅烷与感应染料的摩尔比是2:1 ),以避免在功能化(functionalization )过程中颗粒的过度氨基化。 Using the above method for the same reference dye induction silane binding dye to form a dye conjugate induced, but in this case the molar ratio much lower (i.e., molar ratio of the silane and the dye are induced 2: 1), to avoid over-amination functionalized particles (functionalization) process. 这用于两个目的, 即避免颗粒的团聚及有助于防止表面的氨基抑制感应染料的感应能力。 This serves two purposes, i.e. to avoid agglomeration and amino surfactants help prevent the induction ability to inhibit the induction of dye particles. 此后,感应染坤+结合物与氧化石圭前体在乙醇中以感应染并牛结 Thereafter, the induction dye conjugate + Kun Shi Kyu oxide precursors in ethanol and stained in the induction bovine junction

合物:氧化石圭前体的摩尔比为约1.2 x 10 — 5 M : 0.0125 M下混合。 Compound: a molar ratio of precursor oxide Kyu stone of about 1.2 x 10 - 5 M: 0.0125 M down-mix. 将该混合物逐滴加入到核/壳颗粒的渗析〉容液中。 The mixture was added dropwise to the core / shell particles dialyzed> receiving liquid. 在溶液反应后,其被对(against)乙醇渗析,它可保持稳定至少数月而不发生团聚。 After the reaction solution, which was dialyzed of ethanol (Against), which is stable for at least several months without agglomeration. 在图2A的扫描电镜图中示出的最终颗粒的直径为约40.0nm。 SEM in FIG. 2A, the diameter of the final particles is shown approximately 40.0nm.

通过溶胶-凝胶法制成的核的大小及颗粒的大小是可以改变的。 By the sol - gel process size of the particles and the size of the nucleus can be changed. 导致图1B中示出的颗粒结构的合成如下。 FIG. 1B synthetic particles resulting in the structure shown below. 如上所述,将氧化硅和参比染料结合物在浓度是2.13 xi(T5 M的参比染料结合物、0.2 M 的氧化J圭前体、0.625 M的氨及1.45 M的水的乙醇〉容液中共缩合(co-condense ),以获得直径为约55.0nm的单分散核颗粒。向该混合物中逐滴加入感应染料结合物及另外的氧化硅前体,以获得终反应条件:2.13 x 10 — 5 M的参比染泮牛结合物、2.13 xl(T5 M的感应染泮+结合物、0.254 M的氧化娃前体、0.625 M的氨及1.45 M的水。 这些在核和含有感应染料的外壳之间缺少中间氧化硅壳的颗粒,被离心并在乙醇中及水中各重悬浮两次,以除去过多的试剂。如图2B 所示,最终颗4立的大小为约60.0至80.0nm并具有相对大的富含参比染料的核及富含感应染料的壳。 As described above, the silicon oxide and the reference dye conjugate concentration was 2.13 xi (T5 M reference binding dye composition, Kyu J oxide precursor of 0.2 M, 0.625 M ammonia and 1.45 M water-ethanol> content CCP liquid condensation (co-condense), to obtain a diameter of about 55.0nm monodisperse core particles of this mixture was added dropwise sensor dye conjugate and further a silicon oxide precursor, to obtain a final reaction conditions:. 2.13 x 10 - 5 M reference dye Pan bovine conjugate, 2.13 xl (T5 M induced transfection Pan + conjugate, before oxidation baby 0.254 M of gas, ammonia and water, 1.45 M in 0.625 M of these nuclei and containing a sensing dye. lack of intermediate silicon oxide between the housing shell particles were centrifuged and resuspended twice in each heavy water and ethanol, to remove excess reagent. 2B, the final particle size of about 4 established from 60.0 to 80.0 nm and has a relatively large nucleus and rich reference sensor dye rich shell dye.

图1C所示的氧化硅颗粒结构的制备对上述过程有微小修改。 Preparation of silica particle structure shown in FIG. 1C slight modifications of the above procedure. 氧化石圭前体、氨及水分别以0.17M、 1.0 M、 2.5M的比例在环境条件下在绝对乙醇中通过用力搅拌而结合。 Gui stone oxide precursor, ammonia and water, respectively 0.17M, 1.0 M, was stirred vigorously 2.5M proportion by absolute ethanol at ambient conditions in combination. 在溶液反应后,通过离心收集反应产物,并通过用水和乙醇的超声处理进行重悬浮。 After the reaction solution, the reaction product was collected by centrifugation, and resuspended by sonication in water and ethanol. 接着, 将含有氧化硅的种颗粒在具有水和氨的绝对无水乙醇中再悬浮,随后逐滴加入氧化硅前体、参比结合物及乙醇的预结合溶液,以获得终反应条件:参比结合物、氧化石圭前体、氨及水分别是1.16 M、 0.027 M、 0.2M和2.0M。 Subsequently, the seed particles containing silicon oxide was resuspended in water and absolute ethanol with ammonia, followed by the dropwise addition of the silicon oxide precursor, and a reference pre-conjugate binding ethanol solution to obtain a final reaction conditions: reference The conjugate ratio, stone Kyu oxide precursor, ammonia and water were 1.16 M, 0.027 M, 0.2M and 2.0M. 随后反应12-18小时,4夸颗;粒离心并反复用无水乙醇和去离子水沖洗。 Followed by reaction for 12-18 hours, 4 boast particles; granulating and centrifuged repeatedly with absolute ethanol and deionized water. 使用在乙醇中、在惰性气体中以及有机硅烷与感应染料的摩尔比是50.0 : 1.0的条件下合成出来的感应染料 In ethanol, in an inert gas and the molar ratio of organosilane 50.0 induction dyes are: synthesized under conditions induced dye 1.0

结合物,实施相似的合成方法以在这些颗粒上产生染料壳。 Conjugate, an analogous synthetic methods to produce dye shell on the particles. 如图2C Figure 2C

所示的最终颗粒大小为约200.0nm并含有富含氧化硅的核,其被富含参比染料的第一壳包围,该第一壳被富含感应染料的第二壳包围。 The final particle size of about 200.0nm shown rich core and containing silicon oxide, which is surrounded by rich than the first reference dye shell, the first shell is a second shell surrounding the enriched sensing dye. 在图1D中的第四颗粒的结构中,参比和感应染料层之间的中间氧化硅壳是通过在第一壳上缩聚纯氧化硅前体而引入的,用来确保对包覆的参比染料的进一步保护。 In the fourth structure of the particles in FIG. 1D, a silicon oxide intermediate housing between the reference and sensing the dye layer is formed by polycondensation of pure silicon oxide precursor in the first case introduced, to ensure participation of the coated further protection ratio of the dye.

为了制备本发明的氧化硅基颗粒(使用反月交束来引入缺少合适结合化学物质的染料),微乳液合成方案如下。 To prepare the silica-based particles of the present invention (using anti-cross beams months introducing the lack of suitable chemical binding dye), microemulsion synthetic scheme is as follows. 首先,使用St6ber 溶胶-凝胶法合成具有参比染料的氧化硅基种籽颗粒。 First, St6ber sol - gel method with silicon oxide seed particles reference dye. 将这些种籽颗粒通过渗析或离心及清洗而从乙醇转移到含水环境中。 These seed particles are transferred by dialysis or centrifugation and to wash ethanol from the aqueous environment. 足够的表面涂料所需的反应浓度根据可用的表面硅烷醇基团的数量(依赖于颗粒大小与浓度)来计算。 The reaction concentration required sufficient surface coating according to the number of available surface silanol groups (depending on the particle size and concentration) is calculated. 将颗粒和任何葡聚糖连接物(dextran-bound ) 或其它亲水染料以水溶液形式加入到反相微乳液中,其中该反相微乳液是在环己烷中,在带电荷或不带电荷的两亲表面活性剂存在下,4艮据需要具有或不具有共-表面活性剂下形成的。 The glucan particles and any linker (dextran-bound), or other hydrophilic dye is added as an aqueous solution to a reverse microemulsion, wherein the microemulsion is inverted in cyclohexane, in a charged or uncharged the amphiphilic surfactant is present, Gen 4 as needed with or without co - surfactant formed lower. 加入氨的浓溶、液以4崔4bfU匕石圭前体的缩聚(condensation),其一皮最后力口入。 Concentrated ammonia solution was added, it was 4 to polycondensation stone dagger Kyu Choi 4bfU precursor (condensation), the last one skin force mouth. 一牙中合适的表面活性剂/共表面活性剂的结合是Triton X-100@和正己醇。 A tooth Suitable surfactant / co-surfactant is binding Triton X-100 @, and n-hexanol.

厚度为约2.0至约10.0nm的涂层可以在游离染料分子或葡聚糖连接的染料的存在下有效地附着在颗粒表面,该染料在形成氧化珪基体时净皮捕获,因此,封住感应染料分子并产生颗粒基感应物。 10.0nm thickness is about 2.0 to about coating can be effectively attached to the dye in the presence of free dye molecules or dextran particle surface, the dye formed upon capture net Paper Gui oxide substrate, therefore, the induction seal dye molecules and produce particle-sensing thereof. 换句话说,除了一皮共价连冲妻到氧化硅基基体上,该光致发光染料一^: 被物理捕获或束缚在氧化硅基基体中。 In other words, in addition to a skin punch wife covalently linked to the silicon oxide-based matrix, the photoluminescent dye-^: is captured or trapped in the silicon oxide-based matrix physically. 通过调节反应pH和氧化硅前体的浓度,可调整氧化硅基体的孔隙率,从而使分析物与捕获的染料分子相互作用。 And the pH of the reaction by adjusting the concentration of the silicon oxide precursor, to adjust the porosity of the silica matrix so that the analyte interacts with the dye molecules captured.

在本发明的氧化石圭基颗粒^皮合成后,它们可用于感测生物系统和非生物系统。 After oxidation the stone particles of the present invention Kyu-yl ^ synthetic leather, they may be used to sense non-biological systems and biological systems. 多个感测方法,包4舌比例计量感测、光i普移动感测及寿命感测(life-time sensing )都是可能的。 A plurality of sensing method, including the tongue 4 ratiometric sensing, optical sensing movement of P i and sensing life (life-time sensing) are possible.

环境状态以及某些分析物的存在和浓度,可以在生物和非生物系统中被探测。 Environmental conditions and the presence and concentration of certain analytes, can be detected in biological and non-biological systems. 可以将氧化硅基颗粒引入到细胞、细胞膜、组织、 原核系统(如大肠杆菌生物净皮膜)、溶液、反应和水体,如河和湖中。 Silicon oxide particles may be introduced into cells, cell membranes, tissues, prokaryotic systems (such as Escherichia coli bioscrubber film), a solution, reaction and water, such as river and lake. 已存在多种将氧化硅基颗粒引入到细胞中的方法,包括基于商业可用的脂嚢泡法、显孩t注射和特异性抗体才聂取(在此过程中细胞表面受体介导颗粒的胞吞)。 Silicon oxide, there are multiple particles into a cell, including commercially available fat-based Nang bubble method, which was injected and children t Nie specific antibody was taken (in the process of cell surface receptor-mediated particles endocytosis). 在吞噬细胞和一些内吞细胞中,摄取可以自发地发生。 Phagocytic cells and some cells endocytic uptake may occur spontaneously. 才艮据由颗粒表现的亮度水平,^又通过将单种本发明的氧化硅基颗粒《1入到目标环境中,对于测定是有利的。 Gen only from the particles according to the luminance level of performance, by a single ^ and silicon oxide particles "according to the present invention into a target environment, it is advantageous for the measurement. 然而, 也可4吏用多种氧化;圭基颗粒。 However, it may be oxidized using a variety of 4 officials; Kyu-based particles.

通过将多种类的分析物特异的感应物引入到未知环境中,可以实现多重一全测。 By many types of sensors specific for the analyte is introduced into an unknown environment, we can achieve a full measure multiple. 多重性允许同时探询其发射峰可一皮去巻积的多种光致发光物质从而获得多个分析物的状态。 Multiple simultaneous interrogation allows multiple states photoluminescent material to obtain a plurality of analytes which may be a skin to the emission peak of convolving. 这种方法将非常适合于对细胞功能刺激(如新的治疗法)的影响的高通量分析。 This method is well suited for stimulation effects on cell function (such as a new therapy) of high-throughput analysis.

氧讦匕石圭基颗斗立也可作为感应物用于多种生物体中,在动物细月包或体液中,包4舌人细月包或体液,如血'液或血清中。 Review dagger oxygen Kyu-yl stone particles may also be established as an induction hopper was used in a variety of organisms in animal body fluids or thin month package, the package bag 4 months or fine tongue human body fluids, such as blood 'fluid or serum. 可以4t集细月包或体液并在体外测试,或全身成^象〗义可刺激在体内的染冲+并测量发射 4t can be set and fine month package body fluid or in vitro testing, or into a body〗 ^ sense as in vivo stimulates red dye and measuring the emission at +

波长。 wavelength. 体外感应一^:依赖于含有可见光谱的光致发光染料的感应物。 A ^ vitro induction: the induction was dependent on the photoluminescent dye containing visible spectrum. 在体内测试中,可将感应物局部注射到特定区域,或者用那些表现出与某些细胞表面受体优先相互作用的抗体将感应物功能化。 In vivo test, was induced by local injection may be to a specific area, or by those who exhibit certain cell surface receptors interacting preferentially induced antibody was functional. 用于体内测试的感应染料一^殳表现出红外或近红外发射波长。 Test for in vivo induction ^ Shu dye exhibits a near-infrared or infrared emission wavelength.

处于^皮感应中的环境状态或分冲斤物也可以是不同的。 Sensing ambient conditions in transdermal ^ or pounds red points may also be different. 可以测定如pH水平和疏水的或亲水状态的环境状态。 The pH level can be determined and hydrophobic or hydrophilic environment state state. 例如钾、磷酸才艮、钠、 4丐、铜、《美、4各、氯、氟及4失的离子,例如镉、锌、铅、石西、汞、 4臬的重金属以及生物分子物质,如维生素和氨基酸的存在及浓度也可以被检测。 For example, potassium phosphate was Gen, sodium, 4 cai, copper, "the United States, 4 each, chloro, fluoro, and 4 out of ions, such as cadmium, zinc, lead, Shixi, mercury, 4 provincial judge heavy metals and biological molecular species, the presence and concentration of vitamins and amino acids may also be detected.

而且,用本发明的氧化硅基颗粒进行体外和体内测试对于确定活的生物体中细胞的氧化还原状态是有利的。 Further, in vitro and in vivo test for determining the redox state of cells in a living organism it is advantageous to use silica based particles of the invention. 细胞的氧化还原状态 The redox state of the cell

反映其氧化-还原势能(potential)(即,细胞失去电子(氧化)的电^立(potential)与其获4寻电子(还原)的电^f立(potential)的关系)。 Reflect its oxidation - reduction potential (potential) (ie, cells lose electrons (oxidation) of electricity ^ Li (potential) won its electronic homing 4 (reduction) of the electric relationships ^ f Li (potential) a). 细胞所依赖的能量主要来自于通过氧化反应(从有机分子到氧气, 在细胞内部产生总体的还原环境,其被谨慎地调节)所释放的能量。 Cells depends mainly from the energy by an oxidation reaction (the oxygen from organic molecules to produce an overall reducing environment inside the cell, which is carefully adjusted) energy released. 外界或内部对抗正常的氧化性/还原性的平4軒-氧化还原应激-的攻击已经一皮纟见为对细胞不利事件的指示,尤其是肿瘤发生,并且在疾病或受伤状态如癌症和中风中是非常重要的。 External or internal confrontation normal oxidation / reduction of level 4 Villa - redox stress - the attacks have a skin cell Si see as an indication of adverse events, especially tumors, and disease states such as cancer or injury and stroke is very important.

通过各种感应方法可以研究前述未知的状态或分4斤物。 Unknown can be studied by the various sensors or sub-process state was 4 pounds.

如本文^f吏用的,比率i十量感测(ratiometric sensing)是指基于为已知环境状态并相应于与已知环境状态建立的比率来测定未知的环境状态。 As used herein officials ^ f, i + quantity sensing ratio (ratiometric sensing) means environment state based on the known state of the environment and to the ratio corresponding to the known state of the environment established to determine unknown. 在已知环境或分析物状态下测定两种或多种光致发光染料的主要发射峰强度。 Measuring two or more primary emission peak intensity of the photoluminescence of the dye in a known environment or analyte state. 通过计算两种染料(感应染料/参比染料) By calculating the two dyes (dyes sensing / reference dye)

的山,发射比率而进行才交准;该比率与已知状态相对应。 Hill, emission ratio is performed before cross-registration; known in the ratio corresponding to the state. 该冲交准形成 The registration form punch post

用于测定未知状态的基础,其通过在未知状态下对含有相同参比和感应染料颗粒的激发和发射强度的测量。 Basis for measuring an unknown state, which comprises measuring by the same reference excitation and the induced emission intensity and dye particles in an unknown state.

基于光谱移动的测定是以相似的原理4喿作。 Spectra were measured on movement similar principles as 4 Qiao. 通过使用才交准曲线研究未知环境或分析物状态,其中该校准曲线是基于在已知状态下参比和感应染料被激发所表现出来的最大发射波长而建立起来的。 By using a calibration curve was cross Environment Research unknown or analyte state, wherein the calibration curve is established based on the maximum emission wavelength in a known state and the reference dye is excited by induction manifested. 然而,不是依赖峰值发射强度的比率外,参比和感应染料的最大峰值波长(xmax)之间的差值也被用作因变量。 However, instead of relying on the ratio of the outer peak emission intensity, the difference between the maximum peak wavelength of the reference and sensor dyes (Xmax) is also used as the dependent variable.

基于寿命的感测测定两种或多种光致发光染料的激发态寿命, 它们中的一种的寿命已知对环境是不敏感的,它们中的至少一种的 Based on analyzes of the two or more sensed life excited state lifetime photoluminescent dye, the life of one of them is known to be insensitive to the environment, at least one of them

寿命依赖于具体的环境状态或分析物。 Life depending on the particular environmental conditions or analytes. 荧光寿命(T)是光致发光染 Fluorescence lifetime (T) is a photoluminescent dye

料花费在激发态的时间长度,从开始的光子吸收直到其发射;其最 Feeding the length of time spent in the excited state, from which photon emission until start of absorption; which most

经常在10 ps至婆t纳秒的范围内。 Often 10 ps to the range of nanoseconds po t. 通过测量焚光寿命可以为多种分析物浓度进行校准,为进一步的浓度测定建立基础。 Light burning life may be calibrated for a variety of analyte concentration by measuring, measuring establish a basis for further concentration.

为了为感测建立基线,首先将一个或多个颗粒? To establish a baseline for the senses, first one or more particles? 1入到具有已知状态的环境中。 1 into a known state of the environment. 然后颗粒净皮多光子光源中的一个或多个选4奪的波长 Then 4 wins particles wavelength Pinedo net photon source is selected from one or more of

激发, 一般表现出的激发波长在约250.0 nm至约800.0 nm之间, 这对颗粒中的参比和感应染料的吸收分布图是适当的。 Excitation, typically exhibit excitation wavelength between about 250.0 nm to about 800.0 nm, which absorption profile of the particle sensor and reference dyes are appropriate. 多光子激发利用激光(通常是Ti-蓝宝石),其可以被调成很多种发射波长。 Multi-photon excitation using a laser (typically Ti- Sapphire), which can be transferred into a variety of emission wavelengths. 长波长(700.0 nm到〉1500.0 nm )光子不易一皮组织或培养基吸收,^f旦可能会在染料分子中以非常高的光子流量(即在光束的焦点)引发多光子激发。 Long wavelength (700.0 nm to> 1500.0 nm) photons easily absorb a dermal tissue culture medium or, ^ f denier may be very high photon flux (i.e., in the focus of the beam) initiator multi-photon excitation in the dye molecule. 尽管参比染料一般表现出相对恒定的波长及发射强度,但感应染料却表现出与环境刺激物或某些分析物的存在或浓度相关的发射波长。 Although reference dye typically exhibit a relatively constant emission intensity and wavelength, but has shown induced dye emission wavelength associated with the presence or concentration of certain environmental stimulus or analyte.

因此,在特定水平上;敫发每一种参比和感应染津牛后,就可以测量光子的发射。 Thus, in the particular level; Jiao after hair induction and every reference dye Jin cattle can be measured emission of a photon. 测量可使用荧光分光光度法或荧光显微镜法来实施。 Spectrophotometric measurements using fluorescence microscopy or fluorescence implemented. 光致发光的寿命可使用脉沖激光源和栅极探测器测量,其测量作为时间随照射的函数的发射。 Photoluminescence lifetime using a pulsed laser source can be measured by the detector and the gate, which is measured as a function of irradiation time for transmitting over. 光致发光发射被收集在石英或塑料比色m中,作为与激发束成90度的发射波长的函数(通过在光电倍增管或雪崩光电二极管上的光子计数)。 Photoluminescence emission is collected in a quartz or plastic colorimetric m, as the excitation and emission wavelengths of 90 degrees swept function (photomultiplier tube by photon avalanche photodiode or the count). 使用荧光显微镜法,采集单独的、含有经历不同已知状态的感应物的无细胞样品的图像。 Using fluorescence microscopy, to collect them separately, an image containing a cell-free sample experience different known state of the induction thereof. 在测量参比和感应染料的光子发射后,发射比率(Y - I感应/I参比), 绘出光谱移动或光致发光寿命对于已知环境状态的曲线以建立冲交准曲线。 After induction of photons and measure the reference dye emission, the emission ratio (Y - I induction / I reference), or spectral shifts plotted photoluminescence lifetime versus the known state of the environment to establish a standard curve red cross. 也就是"i兌,在已知环境状态或分析物存在下产生的发射一皮用于产生对照lt据,其与已知状态相关。例如,4交准曲线示出对应于已知环境4犬态的比率范围(^口,在一个具体实施方式中,在约0.5 至约0.8之间的比率可对应于在6至7之间的pH )。 I.e. "i against the emission is generated in a known environmental condition or analyte for generating a control lt transdermal data, which is related to a known state. For example, cross-4 standard curve shows a known environment corresponding to 4 dogs ratio range state (^ port, in a specific embodiment, the ratio is between about 0.5 to about 0.8 may correspond to a pH between 6 and 7).

在产生对照It据后这些据可以用于确定未知的环境状态或分析物的存在及浓度。 It controls data generated after these data may be used to determine the presence and concentration of an unknown environmental conditions or analytes. 在未知状态或分析物存在下记录颗粒的发 Issued presence of particles in a recording state of an unknown or analyte

射,并且通过将其与已知状态下建立的对照数据进行比较而测定未知状态。 Shot, and the unknown state is measured by comparing it against the data established with the known state.

本发明的氧化硅基颗粒可用于各种其它应用,如公开在共同拥 Silica-based particles of the invention may be used in various other applications, as disclosed in commonly owned

有共同申i青的题为"荧光氧化石圭基纳米颗粒(Fluorescent Silica Based Nanoparticles )"的美国申请序列第10/306,614号中的那些。 I Green common application entitled "stone Kyu oxide phosphor-based nanoparticles (Fluorescent Silica Based Nanoparticles)" as those in U.S. Application Serial No. 10 / 306,614.

实施例 Example

以下的实施例用于"i兌明的目的,并不限制本发明。这些实施例并不以任何方式限制本发明或其保护范围。 The following examples serve to "i out against the object, and do not limit the present invention. These examples do not limit the scope of the present invention, or in any manner.

实施例1 (pH感测) Embodiment 1 (pH sensing) Example

合成含有参比染^f和感应染^K基于图1C所示的结构的200.0nm的氧化石圭基颗粒,用作比率计量感应物以一金测环境的pH。 Synthesis and comprising sensing parameters ^ f ^ K oxide-based transfection stone Kyu-yl particle structure shown in FIG. 1C 200.0nm, and it was used as a ratiometric sensor with a pH sensing environment than gold staining.

合成 synthesis

在惰性气氛中,使3-氨基丙基-三乙氧基硅烷(APTS-Sigma Aldrich Chem.Corp.)与参比染料四曱基罗丹明(TRITC)的异石克氰酸酯基团以APTS: TRITO50:l的摩尔比在乙醇(Pharmco 200 proof, 脱气)中偶联以形成TRITC-结合物。 In an inert atmosphere, 3-aminopropyl - (. APTS-Sigma Aldrich Chem.Corp) triethoxysilane and four Yue reference dye rhodamine (TRITC) iso-grams of isocyanate groups to APTS : TRITO50: l mole ratio in ethanol (Pharmco 200 proof, degassed) was coupled to form a conjugate TRITC-. 将该TRITC-结合物在环境气氛下加入到氨(2.0 M乙醇-Sigma Aldrich Chem.Corp.)和水的无水乙醇溶液中,然后其一皮迅速地加入氧化硅前体四乙氧基石圭烷(tetraethoxysilane ) (TEOS-99% Sigma Aldrich Chem.Corp.)以获4寻[TRITC-结合物]、[TEOS]、 [NH3]和[水]分别为1.7 x 10-5 M、 0.17 M、 1.0M和2.5 M的最终反应溶液。 Gui stone tetraethoxysilane was added to the former TRITC- incorporated in an ambient atmosphere to an ammonia (2.0 M ethanol -Sigma Aldrich Chem.Corp.) Solution of water and ethanol, and then quickly added one transdermal silicon oxide precursor alkyl (tetraethoxysilane) (TEOS-99% Sigma Aldrich Chem.Corp.) to obtain 4 hunt [TRITC-conjugate], [TEOS], [NH3] and [water] were 1.7 x 10-5 M, 0.17 M, the final reaction solution of 2.5 M and 1.0M. 该反应进4亍12-18小时,并且通过离心收集混浊的产物并<吏用水和乙醇超声处理而重悬浮。 The reaction is carried out for 12-18 hours right foot 4, and and <officials with water and ethanol sonicated product was collected by centrifugation and resuspended cloudy.

以0.787 mg/ml的浓度在具有合适的水和NH3浓度的无水乙醇中重悬浮这些颗粒,并逐滴(7.5 x lo-7MTEOS/min)加入TEOS、 TRITC-结合物及乙醇的预-结合溶液,以达到[TRITC-结合物]、 [TEOS]、 [NH3]和[水]分别为1.16 mM、 0.27 M、 0.2 M和2.0 M的 To 0.787 mg / ml is suitable anhydrous ethanol having a pre-water and NH3 concentrations were resuspended particles, and added dropwise (7.5 x lo-7MTEOS / min) was added TEOS, TRITC- conjugate and ethanol - binding solution, in order to achieve [TRITC-conjugate], [TEOS], [NH3] and [water] were 1.16 mM, 0.27 M, 0.2 M and 2.0 M of

最纟冬反应条件。 Winter reaction conditions most Si. 然后反应12-18小时,离心这些颗冲立并反复用无水乙醇和去离子水沖洗。 The reaction was then 12-18 hours, these particles washed by centrifugation and washed repeatedly established with absolute ethanol and deionized water.

4吏用在惰性气氛下以4.25 mM FITC1APTS:FITC=50:1的摩尔比合成的FITC结合物,实施相似的合成方法以在这些颗粒上形成荧光(FITC)壳。 4 under an inert atmosphere with officials to 4.25 mM FITC1APTS: FITC = 50: 1 molar ratio of FITC conjugate synthesized, synthesized in a similar method of forming a phosphor on these particles (FITC) shell. 然后,在相似条件下将该结合物加入到以上制备的TRITC结合混合物中,对于0.787 mg/ml的颗粒密度,[FITC-结合物]、[TEOS]、 [NH3]和[水]的最终浓度分别为0.4 mM、 0.029 mM、 0.2 M和2.0 M。 Then, under similar conditions to the TRITC conjugate prepared above was added in the binding mixture, for a particle density of 0.787 mg / ml to, [FITC-conjugate], [TEOS], [NH3] and [water] to a final concentration of respectively, 0.4 mM, 0.029 mM, 0.2 M and 2.0 M. 颗4立大小为约200.0nm (图2C )并含有相只t大的富含参比染料的核及富含感应染料的壳。 Li particle size of about 200.0 4 (FIG. 2C) and only the phase containing a large t-rich core and a reference sensor dye rich shell dye.

校准 calibration

颗粒乂人去离子水中以3:20(v/v)稀释液(dilution )稀释到在pH 5 至pH 9之间的磷酸钠緩冲溶液。 Qe human particles diluted 3:20 in deionized water (v / v) dilution (Dilution) in the sodium phosphate buffer solution at pH between 5 to 9 pH. 然后激发这些颗粒,其通过引入540.0 nm单光子光源来;敫发四甲基罗丹明,以及490 nm来〗敫发荧光素。 These particles are then excited, by the introduction of 540.0 nm single photon light source; Jiao send tetramethylrhodamine, and 490 nm for fluorescein〗 Jiao hair. 发射波长通过荧光光光^普测定法测定(用一台光子冲支术国际荧光光谱测定仪);最大峰在图3中示出。 By measuring the fluorescence emission wavelength spectrophotometer ^ P assay (using a punch branched photon fluorescence spectrometer operation International); the maximum peak shown in Figure 3. 较大波长峰对应于荧光感应染料,而较小的峰对应于四甲基罗丹明参比染料。 Large peak corresponding to wavelength fluorescent dyes induction, while a smaller peak corresponding to reference dye tetramethylrhodamine. 然后,绘制发射波长的最大峰比率(Y = I FITC/ I TRITC )对pH的曲线以给出图4所示的才交准曲线。 Then, the maximum peak emission wavelength draw ratio (Y = I FITC / I TRITC) to give a pH of the curve shown in Figure 4 was cross-calibration curve. 该4交准曲线才是供了对于每组测i式颗并立在pH范围在5-9的线性4交准。 4 is the cross-calibration curve for measurement of particle i of formula 5-9 linear side by side in a quasi-cross-4 in the pH range for each group.

感测 Sensing

可以将以上合成的氧化硅基颗粒卩I入到未知pH的溶液中。 Synthesized above silicon oxide particles may be unknown Jie I into solution pH. 该颗粒可以用在冲交准过程中使用的同样的单光子光源、以相同的激发波长激发。 The particles may be the same source used in single photon cross punch the registration process, at the same excitation wavelength excitation. 然后,可以计算对于发射波长的最大峰比率(Y = IFITC/I TR1TC)并与图4中的校准曲线对比。 Can then be calculated and compared with the calibration curve in FIG. 4 the maximum peak ratio (Y = IFITC / I TR1TC) emission wavelength. 以这种方式,可以测定溶液的pH值。 In this manner, the pH of the solution can be determined.

本领域j支术人员可在不背离本发明4青神和范围的情况下进4亍这里所描述的变更、变形和其它实施方式。 J branched skilled artisan may change into the right foot 4 described herein without departing from the spirit and scope of the Green 4 of the present invention, other modifications and embodiments. 因此,本发明不以〗壬4可方式一皮以上例举性i兌明所限制。 Accordingly, the present invention is not to be〗 nonyl embodiment 4 Exemplary i out against a skin over the limit.

Claims (39)

  1. 1.一种氧化硅基颗粒,包括氧化硅基的核及两种或多种光致发光染料,所述两种或多种光致发光染料含有至少一种参比染料和至少一种感应染料。 A silica-based particles, comprising a core and two kinds or more of silica-based photoluminescent dye, the two or more photoluminescent dyes comprising at least one reference dye and at least one sensor dye .
  2. 2. 根据权利要求1所述的氧化硅基颗粒,其中,所述氧化珪基颗冲立是纳米颗并立。 2. The silica-based particles according to claim 1, wherein said oxide particles yl Gui Li washed nanoparticles are side by side.
  3. 3. 根据权利要求1所述的氧化硅基颗粒,其中,所述氧化硅基颗冲立具有直径在约0.1 nm至约100.0 nm之间的孔。 3. The silica-based particles according to claim 1, wherein the silicon oxide particles having a punched hole between the vertical diameter of from about 100.0 nm to about 0.1 nm.
  4. 4. 根据权利要求1所述的氧化硅基颗粒,其中,所述参比染料和感应染料中至少其一共〗介连4妄至所述氧化石圭基的核。 The silica-based particles according to claim 1, wherein the reference dye and the sensor dye which is connected via a total of at least〗 core 4 to jump the stone Kyu oxide groups.
  5. 5. 根据权利要求1所述的氧化硅基颗粒,其中,所述参比染料和感应染津+中至少其一具有约1.0个至约100.0个之间的染津+分子,并且所述参比染津牛和感应染料响应于在单预定波长发射的单激发源而发射光子。 The silica-based particles according to claim 1, wherein at least one of the reference molecule having between transfected Jin + about 1.0 to about 100.0 dye and dyeing Jin + induction, and the reference Jin emit photons than transfection and induction bovine dye in response to a single excitation source emitting a single predetermined wavelength.
  6. 6. 根据权利要求1所述的氧化硅基颗粒,其中,所述参比染料设置在所述核内并且所述感应染冲+-没置在所述氧化硅基颗粒的至少一部分表面上。 6. The silica-based particles according to claim 1, wherein the reference dye is disposed within the core and the induction transfected red + - not at least a portion of the upper surface of the silicon oxide particles is set at.
  7. 7. 才艮据斥又利要求1所述的氧化硅基颗粒,其中,所述参比染泮牛和感应染津+i殳置在所述核的面上或在所述核的外围。 7. It was Gen claims repellent and the silicon oxide particle of claim 1, wherein said reference and sensing transfection transfected bovine Pan + i Shu Jin placed on a surface of the core or at the periphery of the core.
  8. 8. 根据权利要求1所述的氧化硅基颗粒,进一步包括围绕所述核的氧化硅基的壳,其中,所述参比染剩-没置在所述核内并且所述氧化硅基的壳介于所述参比染料和所述感应染料之间。 8. The silicon oxide based particles according to claim 1, further comprising a silica-based shell surrounding the core, wherein the reference dye remaining - not set and said silicon oxide in said core shell interposed between the reference dye and the sensor dye.
  9. 9.根据权利要求1所述的氧化石圭基颗粒,其中,所述参比染库+和 Gui stone according oxide-based particles according to claim 1, wherein the reference library transfection and +
  10. 10. 根据权利要求1所述的氧化珪基颗粒,其中,所述参比染料和感应染冲牛响应光子暴露的峰^i波长是一皮足够的间隙分开,以至丈能逐个辨别所述发射峰。 10. Gui oxide based particles according to claim 1, wherein the reference dye and the red dye bovine photon induced in response to exposure peak wavelength is separated by a ^ i skin sufficient clearance, as well as feet can individually identify said transmitter peak.
  11. 11. 根据权利要求1所述的氧化硅基颗粒,其中,将所述参比染料或感应染料暴露于光子激发导致红外或近红外发射。 11. The silica-based particles according to claim 1, wherein said reference sensing dye or dye-photon excitation leads to exposure to infrared or near-infrared emission.
  12. 12. 根据权利要求1所述的氧化硅基颗粒,其中,所述感应染料至少对pH、离子的存在和浓度、化学物质或生物化学分析物中的一种有响应。 12. The silica-based particles according to claim 1, wherein said sensing at least in response to one dye on pH, and concentration of ions, chemical or biochemical analytes.
  13. 13. 根据权利要求1所述的氧化硅基颗粒,进一步包括表面改性剂,所述表面改性剂显示出与目标分析物优先相互作用。 13. The silica-based particles according to claim 1, further comprising a surface modifying agent, the surface modifier exhibits preferentially interact with the target analyte.
  14. 14. 根据权利要求1所述的氧化硅基颗粒,进一步包括对疾病状态或损伤有响应的治疗剂。 14. The silica-based particles according to claim 1, further comprising a therapeutic agent that is responsive to a disease state or injury.
  15. 15. —种光致发光纳米颗粒,包括两种或多种光致发光染料及多个孑L,所述两种或多种光致发光染料包含至少一种参比染料和至少一种感应染#+。 15. - seed photoluminescent nanoparticles, comprising two or more photoluminescent dyes and a plurality of larvae L, the two or more photoluminescent dyes comprising at least one reference dye and at least one sensor dye # +.
  16. 16. 根据权利要求15所述的光致发光纳米颗粒,其中,至少一个所述孔的直径在约0.1 nm至约100.0nm之间。 Claim 16. The photoluminescent nanoparticle of claim 15, wherein the at least one aperture diameter between about 0.1 nm to about 100.0nm.
  17. 17. 根据权利要求15所述的光致发光纳米颗粒,其中,所述纳米颗并立的直径在约l.Onm至约250.0nm之间。 17. The photoluminescent nanoparticle of claim 15, wherein said nano-particles side by side in a diameter between about l.Onm to about 250.0nm.
  18. 18. —种方法,包4舌以下步-骤:提供含有两种或多种光致发光染料的至少一种氧化硅基颗粒;将所述至少一种氧化硅基颗粒引入到具有一种或多种未知一犬态或分4斤物的环境中;将所述至少一种氧化硅基颗粒暴露于激发光子,使得所述两种或多种光致发光染料中的每一个发射光子;记录由所述两种或多种光致发光染料发射的每一个光子;测定所述一种或多种未知环境状态或分一斤物。 18. The - method, including the following steps tongue 4 - steps of: providing two or more silicon oxide particles of at least one photoluminescent dye comprising; introducing at least one of the silicon oxide particles to have one or an unknown state or a plurality of divided dogs was 4 pounds in the environment; the at least one silicon oxide particles are exposed to excitation photons, such that the two or more photoluminescent dyes emits photons each; record of each of the two or more photoluminescent dyes photon emitted; assay the one or more states or sub-pound unknown environment thereof.
  19. 19. 才艮据^又利要求18所述的方法,进一步包括在已知环境状态或分析物存在下,用光子激发所述两种或多种光致发光染料。 19. The method according to claim Gen only 18 ^ and claims, further comprising a known environmental condition or analyte, by photon excitation of the two or more photoluminescent dyes.
  20. 20. 根据权利要求19所述的方法,进一步包括比较在所述已知环境状态或分析物存在下获得的所述两种或多种光致发光染料的发射以产生对照数据,并且使所述对照数据与所述已知状态或分析物相关联。 20. The method of claim 19, further comprising two or more photoluminescent dyes emitting comparison ambient conditions in the presence of the analyte of known or obtained to generate control data, and the or analyte status control associated with the known data.
  21. 21. 根据权利要求20所述的方法,其中,所述测定步骤包括使用所述对照lt据来测定未知状态或分4斤物。 21. The method according to claim 20, wherein said determining step comprises measuring lt According to an unknown state or sub-4 pounds purified using the controls.
  22. 22. 根据权利要求18所述的方法,其中,所述测定步骤包括比率计量感测。 22. The method of claim 18, wherein said determining step comprises ratiometric sensing.
  23. 23. 根据权利要求18所述的方法,其中,所述测定步骤包括光谱移动感应。 23. The method of claim 18, wherein said determining step comprises sensing spectral shift.
  24. 24. 根据权利要求18所述的方法,其中,所述测定步骤包括基于寿命的感测。 24. The method according to claim 18, wherein said determining step comprises sensing based life.
  25. 25. 根据权利要求18所述的方法,其中,所述测定步骤发生在体夕卜或体内。 25. The method of claim 18, wherein said measuring step occurs in vivo, or in vivo Bu Xi.
  26. 26. 根据权利要求18所述的方法,其中,所述测定步骤适合于测定氧化还原状态。 26. The method of claim 18, wherein said step of measuring the redox state suitable for measurement.
  27. 27. 根据权利要去18所述的方法,其中,所述两种或多种光致发光染料包括参比染料和感应染料,并且在所述测定步骤中使用单一氧化硅基颗粒。 27. The method of claim 18 go, wherein the two or more photoluminescent dyes comprise a reference dye and a sensor dye, and a single silica-based particle in the measurement step.
  28. 28. 根据权利要求18所述的方法,其中,在所述测定步骤中使用全身成像仪。 28. The method of claim 18, wherein the systemic imager in said measuring step.
  29. 29. 根据权利要求18所述的方法,进一步包括将至少一种氧化硅基颗粒引入到细胞中。 29. The method of claim 18, further comprising at least one silicon oxide particles are introduced into the cells.
  30. 30. 根据据片又利要求18所述的方法,进一步包括用所述至少一种氧化硅基颗粒治疗疾病状态的步骤。 30. The sheet according to another method according to claims 18, further comprising the step of treating a disease condition with the at least one silica-based particles.
  31. 31. 根据权利要求18所述的方法,其中,所述未知状态或分析物选自由pH、疏水性或亲水性环境、氧化还原状态、分析物确定以及分析物浓度组成的组。 31. The method according to claim 18, wherein the unknown state selected from the group consisting of the analyte, or the pH, hydrophobic or hydrophilic environment, redox state, and determining the analyte concentration of an analyte thereof.
  32. 32. 根据权利要求18所述的方法,其中,所述测定步骤包括同时4笨寻多种感应染料,其中所述多种感应染料的发射峰可以被去巻积,用来获得多个未知状态或分析物的状态。 32. The method according to claim 18, wherein said determining step comprises simultaneously searching multiple sensor dyes stupid 4, wherein said plurality of sensing dyes to the emission peaks can be convolving, for obtaining a plurality of unknown status or state analysis thereof.
  33. 33. —种测定生物体未知状态的方法,包括以下步骤:提供含有适合于发射光子的感应染料的氧化硅基纳米颗粒;将所述氧化石圭基纳米颗粒插入到生物体内;用光子激发所述感应染料;测定所述感应染料的发射;以及确定所述生物体的所述未知状态。 33. - Method to Measure an unknown organism state, comprising the steps of: providing a silicon oxide-based nanoparticles containing suitable for emission of a photon induced dye; Gui the oxide-based nanoparticles stone inserted into a living body; photon excitation of the induction dyes; determining the induced emission dye; and determining the unknown condition of the organism.
  34. 34. 根据权利要求33所述的方法,其中,所述氧化硅基纳米颗粒进一步包4舌参比染^"。 34. The method according to claim 33, wherein the silicon oxide-based nanoparticles further reference dye package 4 ^ tongue. "
  35. 35. 根据权利要求33所述的方法,其中,所述氧化硅基纳米颗粒进一步包4舌用于治疗疾病4犬态的治疗剂。 35. The method according to claim 33, wherein the silicon oxide-based nanoparticles further package 4 for the therapeutic agent for diseases of the tongue 4 dogs state.
  36. 36. 根据权利要求33所述的方法,其中,所述未知状态是氧化还原状态。 36. The method according to claim 33, wherein said redox state is an unknown state.
  37. 37. 根据权利要求33所述的方法,其中,所述氧化硅基纳米颗粒一皮i殳置在所述生物体的细胞或组织中。 37. The method of claim 33, wherein the silicon oxide-based nanoparticles disposed in a transdermal i Shu cells or tissues of the organism.
  38. 38. 根据—又利要求33所述的方法,其中,所述氧化石圭基纳米颗粒被设置在所述生物体的血液或其它体液中。 38. - The method of claim 33 further claims, wherein the oxide-based nanoparticles Kyu stone is provided in the blood or other bodily fluids of the organism.
  39. 39. 根据权利要求33所述的方法,其中,所述感应染料在近红外或红外波长处发射。 39. The method according to claim 33, wherein said sensing dye emission in the near infrared or infrared wavelengths at.
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